We wish to explore the significance of the gamma-glutamyl cycle in brain metabolism and its involvement in brain amino acid transport. The activity, distribution and properties of the enzymes of the cycle will be studied in subcellular fractions of the brain, in the choroid plexus and in neurons and glial elements. The acceptor properties of various amino acids and their mutual competition for the amino acid binding site of membrane bound gamma-glutamyl transpeptidase will be determined. Data on cerebral amino acid transport will be correlated with the results of studies on the transpeptidase system. Studies on the further characterization of gamma-glutamyl cyclotransferase from human brain will be pursued and the significance of the different molecular forms of the enzyme will be studied. The in-vivo inhibition of glutathione synthesis in brain by methionine sulfoximine, a potent inhibitor of gamma-glutamyl-cysteine synthetase, and its influence on the entry of amino acids into the central nervous system will be studied and correlated with the convulsions caused by action of this drug. The possibility that the convulsive action of allylglycine is related to its interference with the synthesis of glutathione will be explored. The fate of 5-oxoproline, a metabolic intermediate of the gamma-glutamyl cycle (and which accumulates in a newly described metabolic disorder associated with mental retardation), will be investigated. The influence of several hormones and drugs (known to affect amino acid metabolism and transport) on the synthesis of glutathione and on the activity of the enzymes of the cycle will be tested.